Polyurethane calcification and associated thrombosis remain major obstacles hindering the long term use of polyurethanes in prosthetic valves and ventricular assist systems. Progress in the past three years of this Program has successfully addressed the initial goals of this Program by elucidating the mechanisms of polyurethane calcification and creating synthetic methodology involving hard segment activation to modify (either in bulk or on the surface) already polymerized polyurethanes. Thus, we have created polyurethanes with covalently attached bisphosphonates as effective anticalcification agents. In the Program Continuation, we will address inhibiting thrombus deposition on polyurethane, and thrombus related calcification Aim 1. To derivatize polyurethane with heparin in order to confer relative thrombo-resistance. It is hypothesized that this modification will both reduce platelet-fibrin thrombus build up and retard the development of thrombus associated calcification. Aim 2. Polyurethanes modified with tethered gene vectors to provide local fibrinolysis. This aim will be concerned with modifying the polyurethane surfaces to enable gene transfer of an antibody immobilize gene vector encoding for tissue plasminogen activator (tPA), in order to bring about local fibrinolysis. It is hypothesized that fibrinolysis will help to reduce thrombus buildup. Aim 3. Semilunar cusp replacements combining bisphosphonate, heparin, and local gene therapy to over-express tPA. It is hypothesized that our combined therapeutic modifications to prevent polyurethane cuspal calcification and retard thrombosis, will provide optimal pharmacologic synergy in a sheep pulmonary cusp implant model of polyurethane calcification.